Triethylamine → (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamide

HRID 912456Notes

Reaction equation

HRID 912456 reaction equation
Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11].C(N(CC)CC)C.O=C1CCC(=O)N1[C:26]1[C:34]2[C:29](=[CH:30][C:31]([C:44]([O-])=[O:45])=[C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])[CH:33]=2)[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=1>CN(C)C=O.C(OCC)(=O)C>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[C:44]([NH:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH3:10])[C:4]1=[O:11])=[O:45])[N:28]([CH2:47][CH:48]([CH3:50])[CH3:49])[N:27]=[CH:26]2

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 67416248(3S)-3-amino-1-methylazepan-2-one hydrochlorideHCID 866310512,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate

Product 1

HCID 24864925(S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamideYield 78%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-3-Amino-1-methylazepan-2-one hydrochloride (0.112 g, 0.627 mmol) was dissolved in triethylamine (0.238 mL, 1.71 mmol) and N,N-dimethylformamide (3 mL). To this was added 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (prepared according to Example 16, Step A; 253 mg, 0.570 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by flash chromatography on a silica gel column, eluting with 60% ethyl acetate/hexanes to yield pure (S)-5-(2,4-difluorophenoxy)-1-isobutyl-N-(1-methyl-2-oxoazepan-3-yl)-1H-indazole-6-carboxamide (If) (208 mg, 78%). Mass spec: 471 (M+1). 1H NMR (CDCl3) δ 9.15 (br, 1H), 8.32 (s, 1H), 7.85 (s, 1H), 7.21 (m, 1H), 6.99 (m, 2H), 6.92 (m, 1H), 4.91 (ddd, 1H), 4.21 (d, 2H), 3.67 (dd, 1H), 3.22 (dd, 1H), 3.04 (s, 3H), 2.35 (m, 1H), 2.21 (m, 1H), 2.05-1.81 (m, 3H), 1.54 (m, 1H), 1.45 (m, 1H), 0.92 (d, 6H).

Workup

  1. washwashed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and brine
  2. dry with materialThe organic layer was dried over anhydrous sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude reaction mixture
  6. customwas purified by flash chromatography on a silica gel column
  7. washeluting with 60% ethyl acetate/hexanes

Sources & evidence

ORD record
ord-4893f8fbb51d40d09cd68e7bb434e3c8
Source dataset
uspto-grants-2011_09
Patent number
US08026233B2

Reaction notes

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